Sex-specific pain modulation: The growth factor, neuregulin-1, as a pro-nociceptive cytokine

An increasing amount of evidence indicates that there are significant sex differences in clinical and experimental pain sensitivity in men and women. While it is now clear that the endogenous sex steroids are involved in mediating these sex differences, the cellular and molecular mechanisms that underlie their effects on nociceptive sensitivity remain elusive. Recent studies have shown that sex steroids are potent regulators of gene expression in glial cells, particularly astrocytes. This review specifically highlights some of the evidence of sex steroid regulation of growth factor expression. Growth factors have been shown to be potent pro-nociceptive mediators in rodents. Thus, regulation of their expression by sex steroids may be a general mechanism by which sex steroids exert their effect on pain sensitivity. One such mechanism, the progesterone specific regulation of the growth factor, neuregulin-1, following nerve root injury in the rat, is described in detail. Neuregulin-1 expression is increased in spinal cord astrocytes only in female rats with circulating progesterone. Neuregulin-1 has also been shown to produce transient tactile allodynia when delivered intrathecally in rats. Our understanding of growth factor regulation by sex steroids promises to open up new avenues of investigation into the mechanisms that drive sex differences in pain sensitivity.